Pelvic tumors account for 25% of the 700,000 annual cancer diagnoses in women. Radiotherapy for soft-tissue tumors in the pelvic region increases hip-fracture risk, resulting in substantial patient morbidity and mortality: Treatment for rectal, cervical, and anal cancers in postmenopausal women significantly increases fracture rates by 66%, 65%, and 214%, respectively. Nearly 20% of all women who fracture their hips will not survive one year. Of those who do survive, 85% will not be walking unaided at one year, and most survivors will never return to pre-fracture quality of life. In our preclinical models, ionizing radiation rapidly activated osteoclastic bone resorption and caused a decline in trabecular-bone volume fraction of 20-30% during the seven to fourteen days after exposure. Increased expression of proinflammatory cytokines in the marrow preceded activation of osteoclasts, which was followed by evidence (indicated by phosphoSmad2) of activated transforming growth factor-beta (TGF) signaling. In companion studies, the loss in trabecular-bone volume fraction was prevented by the bisphosphonate risedronate. Our recently completed clinical trial confirms rapid bone loss in patients receiving radiation therapy for gynecological tumors: We observed a 14% decline in proximal femur bone mineral content (BMC). No prophylactic treatment exists for radiation therapy-induced osteoporosis, and molecular mechanisms for this rapid loss of bone mass and strength and resultant increased fracture risk are unknown. We propose that radiation therapy in women with pelvic tumors causes a rapid decline in bone mass that leads to increased fracture risk. We hypothesize that the causal mechanism for this radiation-induced deficit in bone quality is rapid activation (from bone-marrow's early inflammatory response to radiation damage) of osteoclasts via the cytokines tumor necrosis factor-alpha (TNFa) and interleukin-1 (IL-1). Estrogen suppression enhances this inflammatory response by promoting greater phagocyte infiltration. Furthermore, the subsequent release of TGF from resorbed bone matrix propagates and accelerates bone loss by increasing osteoclastic bone resorption and inhibiting osteoblast differentiation. Existing therapies for osteoporosis and other disorders (e.g., the antiresorptive zoledronate, RANKL-blocking osteoprotegerin (OPG), TNFa binding protein [TNFbp], IL-1 receptor antagonist [IL-1ra], and a TGF receptor I kinase inhibitor) may prevent this bone loss and could be rapidly translated to clinical treatment. To test this causal-mechanism hypothesis, the following specific Aims will determine 1) If greater levels of activated TGF exacerbate radiation-induced bone loss; 2) The role of inflammatory cytokines TNFa and IL-1 in acute radiation-induced activation of osteoclastic bone resorption; 3) If osteoclast-inhibiting therapies preserve bone mass in a mouse model for radiation-induced bone loss in the setting of estrogen deficiency. By addressing an unstudied biomedical problem that we have already translated to a clinical trial, this innovative proposal's clinical impact could reduce the risk of cancer treatment-related morbidity such as radiation therapy-induced fractures. The cause of these fractures is poorly understood, and no preventative therapies are in use. If radiation therapy increases fracture risk by activating osteoclastic bone resorption, existing antiresorptive osteoporosis therapies should prevent radiation therapy-induced fractures. PUBLIC HEALTH RELEVANCE: Radiotherapy of soft-tissue tumors in the pelvic region increases risk of hip-fracture, and fractures result in substantial patient morbidity and mortality. In a novel approach to the study of radiotherapy's long-term effects on health, the activation of osteoclasts by ionizing radiation and the resultant profound decline in bone mass are confirmed in a completed clinical trial. The overall goal of this research is to rapidly translate this group's ongoing preclinical and clinical research in radiation-induced bone loss into a treatment regimen that reduces fracture risk in women who receive ionizing radiation for pelvic tumors.